The present invention relates generally to enantioselective processes for preparing .alpha.-substituted or .alpha.,.alpha.-disubstituted amino acid derivatives, and more particularly to such processes achieving improved enantioselectivity and catalysts for the same.
As further background, the utilization of natural and unnatural .alpha.-amino acids in practically all areas of the physical and life sciences continues to grow. In addition to their key biological role as the "building blocks" of peptides, proteins and other natural products, the .alpha.-amino acids are used extensively in the pharmaceutical, agrochemical and food industries.
They have also been used in total synthesis and other synthetic studies, both as sources of chirality in final products and as chiral auxiliaries, reagents and catalysts for asymmetric synthesis. Because of this widespread use, new and versatile methods for both the small and large scale preparation of natural as well as structurally diversified .alpha.-amino acid derivatives are important. Methods for the asymmetric synthesis of .alpha.-amino acids that involve catalytic enantiocontrol are one area of interest. See, generally, "Synthesis of Optically Active .alpha.-Amino Acids," R. M. Williams, Pergamon, Oxford, 1989.
In the area of carbon-carbon bond formation involving the reaction of .alpha.-anionic synthons of glycine or higher amino acids, a synthesis of .alpha.-monoalkyl amino acids using catalytic phase-transfer (PTC) alkylations of the benzophenone imine of certain glycine alkyl esters and other glycine synthons has been reported. M. J. O'Donnell, J. M. Boniece and S. E. Earp, Tetrahedron Lett., 1978, 2641; M. J. O'Donnell and T. M. Eckrich, Tetrahedron Lett., 1978, 4625; L. Ghosez, J.-P. Antoine, E. Defense, M. Navarro, V. Libert, M. J. O'Donnell, W. A. Bruder, K. Willey and K. Wojciechowski, Tetrahedron Lett., 1982, 23, 4255.
As advantages, in contrast to known anhydrous alkylative routes, the PTC method involves a simple reaction procedure, mild conditions, inexpensive and safe reagents and solvents, commercially available starting substrates and the ability to easily scale-up the reaction. Since there was no chirality control element used in these early reactions, the products are racemic mixtures (50:50 mixture of two enantiomers). The method has been extended to the alkylation of certain aldimine derivatives as a route to .alpha.,.alpha.-dialkyl amino acids (here exemplified by a racemic synthesis of certain .alpha.-methyl amino acids). M. J. O'Donnell, B. LeClef, D. B. Rusterholz, L. Ghosez, J.-P. Antoine and M. Navarro, Tetrahedron Lett., 1982, 23, 4259; M. J. O'Donnell and D. B. Rusterholz, Synth. Commun., 1989, 19, 1157. These phase transfer alkylations have been conducted under a variety of mild, basic conditions (M. J. O'Donnell, J. M. Boniece and S. E. Earp, Tetrahedron Lett., 1978, 2641; M. J. O'Donnell and T. M. Eckrich, Tetrahedron Lett., 1978, 4625; L. Ghosez, J.-P. Antoine, E. Defense, M. Navarro, V. Libert, M. J. O'Donnell, W. A. Bruder, K. Willey and K. Wojciechowski, Tetrahedron Lett., 1982, 23, 4255; M. J. O'Donnell, W. Bruder, K. Wojciechowski, L. Ghosez, M. Navarro, F. Sainte and J.-P. Antoine, Peptides: Structure and Function, Proc. 8th Amer. Pept. Symp., 1983, 151; M. J. O'Donnell, K. Wojciechowski, L. Ghosez, M. Navarro, F. Sainte and J.-P. Antoine, Synthesis, 1984, 313.) and other interesting amino acids, such as 1-aminocyclopropane-1-carboxylic acid, (M. J. O'Donnell, W. A. Bruder, T. M. Eckrich, D. F. Schullenberger and G. S. Staten, Synthesis, 1984, 127.) and 3-fluorophenylalanine (M. J. O'Donnell, C. L. Barney and J. R. McCarthy, Tetrahedron Lett., 1985, 26, 3067.) have been prepared using this procedure.
An asymmetric synthesis of .alpha.-amino acids by phase-transfer catalysis (PTC) was reported by M. J. O'Donnell, W. D. Bennett and S. Wu, J. Am. Chem. Soc., 1989, 111, 2353 [see "Phase-Transfer Catalysis Offers Practical .alpha.-Amino Acid Synthesis," Chemical & Engineering News, Apr. 10, 1989, pages 25-27 for an article about this paper]. The methodology developed using early catalytic systems allowed preparation of either enantiomer of a several types of target amino acids in up to 66% enantiomeric excess ("ee") (an 83:17 mixture of enantiomers). The method used catalytic amounts of pseudoenantiomeric phase-transfer catalysts 1 and 2. These catalysts and their precursors, cinchonine and cinchonidine, respectively, are inexpensive and commercially available. ##STR1##
The ability to scale the reaction up and the possibility of preparing (.alpha.-amino acids in good optical purity were demonstrated by the synthesis of 6.5 g of optically pure non-natural 4-chloro-D-phenylalanine (R-4, R=4-ClC.sub.6 H.sub.4 CH.sub.2) from the starting substrate 3 (R'=tBu). M. J. O'Donnell, W. D. Bennett and S. Wu, J. Am. Chem. Soc., 1989, 111, 2353 [see "Phase-Transfer Catalysis Offers Practical .alpha.-Amino Acid Synthesis," Chemical Engineering News, Apr. 10, 1989, pages 25-27 for an article about this paper]. By changing from the cinchonine- (1) to the cinchonidine-derived catalyst series (2), the optically pure enantiomeric product (S-4, R'=4CIC.sub.6 H.sub.4 CH.sub.2) could also be prepared by this procedure. ##STR2##
The PTC methodology has recently been extended to the synthesis of .alpha.-methyl amino acids (M. J. O'Donnell and S. Wu, Tetrahedron: Asymmetry, 1992, 3, 591.), an important class of unnatural amino acid derivatives. For example, 5 (Ar=4-ClC.sub.6 H.sub.4, R'=tBu) was alkylated with 4-fluorobenzyl bromide in the presence of a catalytic amount of N-benzylcinchoninium chloride (1, X=Cl) to give the .alpha.-methyl-4-fluoro-R-phenylalanine derivative in 50% enantioselectivity (75:25 mixture of enantiomers). ##STR3##
A review of enantioselective syntheses in the presence of phase transfer catalysts is found in M. J. O'Donnell, "Asymmetric Phase Transfer Reactions," in Catalytic Asymmetric Synthesis, I. Ojima, Ed., VCH, New York, 1993.
In light of this background there remain needs for improved processes for producing .alpha.-amino acid derivatives, catalysts providing improved enantioselectivity, and precursors to .alpha.-amino acid derivatives. The present invention addresses these needs.